Clinical translation of noninvasive intracranial pressure sensing with diffuse correlation spectroscopy.

OBJECTIVE: Intracranial pressure (ICP) is an important therapeutic target in many critical neuropathologies. The current tools for ICP measurements are invasive; hence, these are only selectively applied in critical cases where the benefits surpass the risks. To address the need for low-risk ICP monitoring, the authors developed a noninvasive alternative. METHODS: The authors recently demonstrated noninvasive quantification of ICP in an animal model by using morphological analysis of microvascular cerebral blood flow (CBF) measured with diffuse correlation spectroscopy (DCS). The current prospective observational study expanded on this preclinical study by translating the method to pediatric patients. Here, the CBF features, along with mean arterial pressure (MAP) and heart rate (HR) data, were used to build a random decision forest, machine learning model for estimation of ICP; the results of this model were compared with those of invasive monitoring. RESULTS: Fifteen patients (mean age ± SD [range] 9.8 ± 5.1 [0.3-17.5] years; median age [interquartile range] 11 [7.4] years; 10 males and 5 females) who underwent invasive neuromonitoring for any purpose were enrolled. Estimated ICP (ICPest) very closely matched invasive ICP (ICPinv), with a root mean square error (RMSE) of 1.01 mm Hg and 95% limit of agreement of ≤ 1.99 mm Hg for ICPinv 0.01-41.25 mm Hg. When the ICP range (ICPinv 0.01-29.05 mm Hg) was narrowed on the basis of the sample population, both RMSE and limit of agreement improved to 0.81 mm Hg and ≤ 1.6 mm Hg, respectively. In addition, 0.3% of the test samples for ICPinv ≤ 20 mm Hg and 5.4% of the test samples for ICPinv > 20 mm Hg had a limit of agreement > 5 mm Hg, which may be considered the acceptable limit of agreement for clinical validity of ICP sensing. For the narrower case, 0.1% of test samples for ICPinv ≤ 20 mm Hg and 1.1% of the test samples for ICPinv > 20 mm Hg had a limit of agreement > 5 mm Hg. Although the CBF features were crucial, the best prediction accuracy was achieved when these features were combined with MAP and HR data. Lastly, preliminary leave-one-out analysis showed model accuracy with an RMSE of 6 mm Hg and limit of agreement of ≤ 7 mm Hg. CONCLUSIONS: The authors have shown that DCS may enable ICP monitoring with additional clinical validation. The lower risk of such monitoring would allow ICP to be estimated for a wide spectrum of indications, thereby both reducing the use of invasive monitors and increasing the types of patients who may benefit from ICP-directed therapies.

Using near-infrared spectroscopy and a random forest regressor to estimate intracranial pressure.

Significance: Intracranial pressure (ICP) measurements are important for patient treatment but are invasive and prone to complications. Noninvasive ICP monitoring methods exist, but they suffer from poor accuracy, lack of generalizability, or high cost. Aim: We previously showed that cerebral blood flow (CBF) cardiac waveforms measured with diffuse correlation spectroscopy can be used for noninvasive ICP monitoring. Here we extend the approach to cardiac waveforms measured with near-infrared spectroscopy (NIRS). Approach: Changes in hemoglobin concentrations were measured in eight nonhuman primates, in addition to invasive ICP, arterial blood pressure, and CBF changes. Features of average cardiac waveforms in hemoglobin and CBF signals were used to train a random forest (RF) regressor. Results: The RF regressor achieves a cross-validated ICP estimation of 0.937 r 2 , 2.703 - mm Hg 2 mean squared error (MSE), and 95% confidence interval (CI) of [ - 3.064 3.160 ] mmHg on oxyhemoglobin concentration changes; 0.946 r 2 , 2.301 - mmHg 2 MSE, and 95% CI of [ - 2.841 2.866 ] mmHg on total hemoglobin concentration changes; and 0.963 r 2 , 1.688 mmHg 2 MSE, and 95% CI of [ - 2.450 2.397 ] mmHg on CBF changes. Conclusions: This study provides a proof of concept for the use of NIRS in noninvasive ICP estimation.

Nanoceria: Metabolic interactions and delivery through PLGA-encapsulation.

Cerium oxide nanoparticles (nanoceria) have recyclable antioxidative activity. It has numerous potential applications in biomedical engineering, such as mitigating damage from burns, radiation, and bacterial infection. This mitigating activity is analogous to that property of metabolic enzymes such as superoxide dismutase (SOD) and catalase - scavengers of reactive oxygen species (ROS). Therefore, nanoceria can protect cells from environmental oxidative stress. This therapeutic effect prompted studies of nanoceria and metabolic enzymes as a combination therapy. The activity and structure of SOD, catalase, and lysozyme were examined in the presence of nanoceria. A complementary relationship between SOD and nanoceria motivated the present work, in which we explored a method for simultaneous delivery of SOD and nanoceria. The biocompatibility and tunable degradation of poly(lactic-co-glycolic acid) (PLGA) made it a candidate material for encapsulating both nanoceria and SOD. Cellular uptake studies were conducted along with a cytotoxicity assay. The antioxidative properties of PLGA-nanoceria-SOD particles were verified by adding H2O2 to cell culture and imaging with fluorescent markers of oxidative stress. Our results suggest that PLGA is a suitable encapsulating carrier for simultaneous delivering nanoceria and SOD together, and that this combination effectively reduces oxidative stress in vitro.